Pavlovian Conditioning Paradigm Research Articles

Exaggerated sensitivity to threat and reduced medial prefrontal engagement during threat generalization in reactive aggressive adolescents

Aggressive adolescents tend to exhibit abnormal fear acquisition and extinction, and reactive aggressive adolescents are often more anxious. However, the relationship between fear generalization and reactive aggression (RA) remains unknown. According to Reactive-Proactive Aggression Questionnaire (RPQ) scores, 61 adolescents were divided into two groups, namely, a high RA group (N = 30) and a low aggression (LA) group (N = 31). All participants underwent three consecutive phases of the Pavlovian conditioning paradigm (i.e., habituation, acquisition, and generalization), and neural activation of the medial prefrontal cortex (mPFC) was assessed by functional near-infrared spectroscopy (fNIRS). The stimuli were ten circles with varying sizes, including two conditioned stimuli (CSs) and eight generalization stimuli (GSs). A scream at 85 dB served as the auditory unconditioned stimulus (US). The US expectancy ratings of both CSs and GSs were higher in the RA group than in the LA group. The fNIRS results showed that CSs and GSs evoked lower mPFC activation in the RA group compared to the LA group during fear generalization. These findings suggest that abnormalities in fear acquisition and generalization are prototypical dysregulations in adolescents with RA. They provide neurocognitive evidence for dysregulated fear learning in the mechanisms underlying adolescents with RA, highlighting the need to develop emotional regulation interventions for these individuals.

The effect of social anxiety on threat acquisition and extinction: a systematic review and meta-analysis.

Although exposure-based therapy has been found to be effective at alleviating symptoms of social anxiety disorder, it often does not lead to full remission, and relapse after treatment is common. Exposure therapy is based on theoretical principles of extinction of conditioned fear responses. However, there are inconsistencies in findings across experiments that have investigated the effect of social anxiety on threat conditioning and extinction processes. This systematic review and meta-analysis aimed to examine whether elevated levels of social anxiety are associated with abnormalities in threat conditioning and extinction processes. A second aim was to examine the sensitivity of various study designs and characteristics to detect social anxiety-related differences in threat conditioning and extinction. A systematic search was conducted, which identified twenty-three experiments for inclusion in the review. The findings did not demonstrate compelling evidence that high levels of social anxiety are associated with atypical threat conditioning or extinction. Further, when systematically examining the data, there was no convincing support that the use of a particular psychophysiological measure, subjective rating, or experimental parameter yields more consistent associations between social anxiety and conditioning processes during threat acquisition or extinction. Meta-analyses demonstrated that during threat extinction, the use of anxiety ratings as a dependent variable, socially relevant unconditioned stimuli, and a higher reinforcement schedule produced more detectable effects of social anxiety on compromised extinction processes compared to any other dependent variable (subjective or physiological) or experimental parameter. Overall, the results of this study suggest that social anxiety is not reliably related to deficits in conditioning and extinction processes in the context of laboratory-based Pavlovian conditioning paradigms.

A multi-modal assessment of fear conditioning in adolescent anorexia nervosa.

Anorexia nervosa (AN) is a pernicious psychiatric disorder which is principally characterized by a fear of weight gain. Notwithstanding the centrality of fear in the psychopathology of AN, controlled assessments of negative valence systems are lacking. Herein we assess fear conditioning in adolescent females with AN. Adolescent girls (Mage = 14.6 years, ±1.57) with DSM-5 diagnoses of AN (N = 25) and age-matched control girls (Mage = 14.8 years, ±1.46) with no DSM-5 diagnoses (N = 25) completed structured clinical interviews and participated in a classical three-phase Pavlovian fear conditioning paradigm. Participants with comorbid anxiety disorders were excluded. Skin conductance response (SCR) was measured, alongside self-reported fear, valence, and fear expectancy ratings. Both groups demonstrated significant differential acquisition across all four measures. Regarding group comparisons, no differences emerged for self-reported fear, valence, and fear expectancy ratings during acquisition, although for SCR, those with AN demonstrated reduced physiological arousal relative to controls. Both groups demonstrated significant differential extinction for unconditioned stimuli (US) expectancy, self-report fear, and self-report valence. No statistically significant group differences were evident during extinction to the conditioned stimuli (CS)+, on any outcome measure. However, controls reported more positive valence to the CS- than those with AN. Contrary to our hypotheses, our preliminary assessment did not find support for elevated fear responding among adolescent girls with AN with regards to fear acquisition or extinction. These data suggest that AN in adolescent girls may not be associated with a heightened propensity to acquire fear, but conversely, may suggest that exposure treatments for AN may be helpful, since extinction learning is intact in AN. AN is characterized by fear-related symptoms, including food and weight-related fear, and behavioral avoidance, yet controlled studies assessing fear learning are limited. Our preliminary assessment of adolescent AN indicates no abnormalities in fear learning among adolescents with AN. These findings may inform existing mechanistic models of AN psychopathology, and the development of exposure-based treatments for AN.

Risk-promoting effects of reward-paired cues in human sign- and goal-trackers

Animal research suggests trait-like individual variation in the degree of incentive salience attribution to reward-predictive cues, defined phenotypically as sign-tracking (high) and goal-tracking (low incentive salience attribution). While these phenotypes have been linked to addiction features in rodents, their translational validity is less clear. Here, we examined whether sign- and goal-tracking in healthy human volunteers modulates the effects of reward-paired cues on decision making. Sign-tracking was measured in a Pavlovian conditioning paradigm as the amount of eye gaze fixation on the reward-predictive cue versus the location of impending reward delivery. In Study 1 (Cherkasova et al., 2018), participants were randomly assigned to perform a binary choice task in which rewards were either accompanied (cued, n = 63) or unaccompanied (uncued, n = 68) by money images and casino jingles. In Study 2, participants (n = 58) performed cued and uncued versions of the task in a within-subjects design. Across both studies, cues promoted riskier choice. Sign-tracking was not associated with risky choice in either study. Goal-tracking rather than sign-tracking was significantly associated with greater risk-promoting effects of cues in Study 1 but not in Study 2, although the direction of findings was consistent across both studies. These findings are at odds with the notion of sign-trackers being preferentially susceptible to the influence of reward cues on behavior and point to the role of mechanisms besides incentive salience in mediating such influences.

Sign-tracking and goal-tracking in humans: Utilising eye-tracking in clinical and non-clinical populations

BackgroundIn Pavlovian conditioning, learned behaviour varies according to the perceived value of environmental cues. For goal-trackers (GT), the cue merely predicts a reward, whilst for sign-trackers (ST), the cue holds incentive value. The sign-tracking/goal-tracking model is well-validated in animals, but translational work is lacking. Despite the model’s relevance to several conditions, including attention deficit hyperactivity disorder (ADHD), we are unaware of any studies that have examined the model in clinical populations. MethodsThe current study used an eye-tracking Pavlovian conditioning paradigm to identify ST and GT in non-clinical (N = 54) and ADHD (N = 57) participants. Eye movements were recorded whilst performing the task. Dwell time was measured for two areas of interest: sign (i.e., cue) and goal (i.e., reward), and an eye-gaze index (EGI) was computed based on the dwell time sign-to-goal ratio. Higher EGI values indicate sign-tracking behaviour. ST and GT were determined using median and tertiary split approaches in both samples. ResultsDespite greater propensity for sign-tracking in those with ADHD, there was no significant difference between groups. The oculomotor conditioned response was reward-specific (CS+) and present, at least partly, from the start of the task indicating dispositional and learned components. There were no differences in externalising behaviours between ST and GT for either sample. ConclusionsSign-tracking is associated with CS+ trials only. There may be both dispositional and learned components to sign-tracking, potentially more common in those with ADHD. This holds translational potential for understanding individual differences in reward-learning.

Sex-biased effects of outcome devaluation by sensory-specific satiety on Pavlovian-conditioned behavior.

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.

A new experimental rat model of nocebo-related nausea involving double mechanisms of observational learning and conditioning.

The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms. Male Sprague-Dawley rats with nitroglycerin-induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms. Both strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5-hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c-Fos-positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus-dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days. The present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.

LIM-kinase 1 effects on memory abilities and male courtship song in Drosophila depend on the neuronal type.

The signal pathway of actin remodeling, including LIM-kinase 1 (LIMK1) and its substrate cofilin, regulates multiple processes in neurons of vertebrates and invertebrates. Drosophila melanogaster is widely used as a model object for studying mechanisms of memory formation, storage, retrieval and forgetting. Previously, active forgetting in Drosophila was investigated in the standard Pavlovian olfactory conditioning paradigm. The role of specific dopaminergic neurons (DAN) and components of the actin remodeling pathway in different forms of forgetting was shown. In our research, we investigated the role of LIMK1 in Drosophila memory and forgetting in the conditioned courtship suppression paradigm (CCSP). In the Drosophila brain, LIMK1 and p-cofilin levels appeared to be low in specific neuropil structures, including the mushroom body (MB) lobes and the central complex. At the same time, LIMK1 was observed in cell bodies, such as DAN clusters regulating memory formation in CCSP. We applied GAL4 × UAS binary system to induce limk1 RNA interference in different types of neurons. The hybrid strain with limk1 interference in MB lobes and glia showed an increase in 3-h short-term memory (STM), without significant effects on long-term memory. limk1 interference in cholinergic neurons (CHN) impaired STM, while its interference in DAN and serotoninergic neurons (SRN) also dramatically impaired the flies' learning ability. By contrast, limk1 interference in fruitless neurons (FRN) resulted in increased 15-60 min STM, indicating a possible LIMK1 role in active forgetting. Males with limk1 interference in CHN and FRN also showed the opposite trends of courtship song parameters changes. Thus, LIMK1 effects on the Drosophila male memory and courtship song appeared to depend on the neuronal type or brain structure.

Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder

Failure to successfully extinguish fear is a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). PTSD is also characterized by dysfunctional corticolimbic activation and connectivity. The endocannabinoid system is a putative system to target for rescuing these behavioral and neural deficits. In healthy adults, acute, low-dose delta-9-tetrahydrocannabinol (THC) facilitates fear extinction and increases cortico-limbic activation and connectivity in response to threat. The present study determines the effect of acute, low-dose THC on fear-related brain activation and connectivity during fear extinction in trauma-exposed adults with (PTSD = 19) and without PTSD [trauma-exposed controls (TEC) = 26] and non-trauma-exposed [healthy controls (HC) = 26]. We used a Pavlovian fear conditioning and extinction paradigm, where we measured concurrent functional magnetic resonance imaging (fMRI) and behavioral responses (i.e., skin conductance responding and expectancy ratings). Using a randomized, double-blind, placebo-controlled design, N = 71 subjects were randomized to receive placebo (PBO, n = 37) or THC (n = 34) prior to fear extinction learning. During early extinction learning, individuals with PTSD given THC had greater vmPFC activation than their TEC counterparts. During a test of the return of fear (i.e., renewal), HC and individuals with PTSD given THC had greater vmPFC activation compared to TEC. Individuals with PTSD given THC also had greater amygdala activation compared to those given PBO. We found no effects of trauma group or THC on behavioral fear indices during extinction learning, recall, and fear renewal. These data suggest that low dose, oral THC can affect neural indices of fear learning and memory in adults with trauma-exposure; this may be beneficial for future therapeutic interventions seeking to improve fear extinction learning and memory.

Absence of VGLUT3 Expression Leads to Impaired Fear Memory in Mice.

Fear is an emotional mechanism that helps to cope with potential hazards. However, when fear is generalized, it becomes maladaptive and represents a core symptom of posttraumatic stress disorder (PTSD). Converging lines of research show that dysfunction of glutamatergic neurotransmission is a cardinal feature of trauma and stress related disorders such as PTSD. However, the involvement of glutamatergic co-transmission in fear is less well understood. Glutamate is accumulated into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The atypical subtype, VGLUT3, is responsible for the co-transmission of glutamate with acetylcholine, serotonin, or GABA. To understand the involvement of VGLUT3-dependent co-transmission in aversive memories, we used a Pavlovian fear conditioning paradigm in VGLUT3-/- mice. Our results revealed a higher contextual fear memory in these mice, despite a facilitation of extinction. In addition, the absence of VGLUT3 leads to fear generalization, probably because of a pattern separation deficit. Our study suggests that the VGLUT3 network plays a crucial role in regulating emotional memories. Hence, VGLUT3 is a key player in the processing of aversive memories and therefore a potential therapeutic target in stress-related disorders.

Implicit threat learning involves the dorsolateral prefrontal cortex and the cerebellum

Background/ObjectiveMost studies investigating the neural correlates of threat learning were carried out using an explicit Pavlovian conditioning paradigm where declarative knowledge on contingencies between conditioned (CS) and unconditioned stimuli (US) is acquired. The current study aimed at understanding the neural correlates of threat conditioning when contingency awareness is limited or even absent. MethodWe conducted an fMRI report of threat learning in an implicit associative learning paradigm called multi-CS conditioning, in which a number of faces were associated with aversive screams (US) such that participants could not report contingencies between the faces and the screams. ResultsThe univariate results showed support for the recruitment of threat-related regions including the dorsolateral prefrontal cortex (dlPFC) and the cerebellum during acquisition. Further analyses by the multivariate representational similarity technique identified learning-dependent changes in the bilateral dlPFC. ConclusionOur findings support the involvement of the dlPFC and the cerebellum in threat conditioning that occurs with highly limited or even absent contingency awareness.

Encoding of conditioned inhibitors of fear in the infralimbic cortex.

Cues in the environment signaling the absence of threat, i.e. safety, can influence both fear and reward-seeking behaviors. Heightened and maladaptive fear is associated with reduced activity in the medial prefrontal cortex. We have previously shown in male rats that the infralimbic (IL) prefrontal cortex is necessary for suppressing fear during a safety cue. The objective of the present study was to determine if there was safety cue-specific neural activity within the IL using a Pavlovian conditioning paradigm, where a fear cue was paired with shock, a safety cue was paired with no shock, and a reward cue was paired with sucrose. To investigate how safety cues can suppress fear, the fear and safety cues were presented together as a compound fear + safety cue. Single-unit activity showed a large proportion of neurons with excitatory responses to the fear + safety cue specifically, a separate group of neurons with excitatory responses to both the reward and fear + safety cues, and bidirectional neurons with excitation to the fear + safety cue and inhibition to the fear cue. Neural activity was also found to be negatively correlated with freezing during the fear + safety cue. Together, these data implicate the IL in encoding specific aspects of conditioned inhibitors when fear is being actively suppressed.

The causal role of affect sharing in driving vicarious fear learning.

Vicarious learning, i.e. learning through observing others rather than through one's own experiences, is an integral skill of social species. The aim of this study was to assess the causal role of affect sharing, an important aspect of empathy, in vicarious fear learning. N = 39 participants completed a vicarious Pavlovian fear conditioning paradigm. In the learning stage, they watched another person-the demonstrator-responding with distress when receiving electric shocks to a color cue (conditioned stimulus; CS+; a different color served as CS-). In the subsequent test stage, an increased skin conductance response (SCR) to the CS+ presented in the absence of the demonstrator indexed vicarious fear learning. Each participant completed this paradigm under two different hypnotic suggestions, which were administered to induce high or low affect sharing with the demonstrator in the learning stage, following a counterbalanced within-subject design. In the learning stage, high affect sharing resulted in stronger unconditioned SCR, increased eye gaze toward the demonstrator's face, and higher self-reported unpleasantness while witnessing the demonstrator's distress. In the test stage, participants showed a stronger conditioned fear response (SCR) when they had learned under high, compared to low, affect sharing. In contrast, participants' declarative memory of how many shocks the demonstrator had received with each cue was not influenced by the affect sharing manipulation. These findings demonstrate that affect sharing is involved in enhancing vicarious fear learning, and thus advance our understanding of the role of empathy, and more generally emotion, in social observational learning.

Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality Pavlovian fear extinction paradigm in healthy adults

Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.

Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects.

Background: 3,4-Methylenedioxymethamphetamine (MDMA) has shown initial promise as an adjunct in psychotherapy to treat posttraumatic stress disorder (PTSD). Its efficacy and safety have been demonstrated across phase I–III studies. However, the mechanism underlying the potential utility of MDMA to treat PTSD in humans has not yet been thoroughly investigated. Preliminary evidence suggests that MDMA may facilitate fear extinction recall, which may be through the release of oxytocin. To test this hypothesis, we examined the efficacy of acute MDMA treatment to enhance fear extinction learning and recall. Methods: We used a two-period, double-blind, randomized, placebo-controlled crossover design in 30 healthy male subjects who received a placebo and a single dose of MDMA (125 mg). Fear extinction was tested using two separate Pavlovian fear conditioning paradigms, one using skin conductance response (SCR), and the other fear-potentiated startle (FPS) to conditioned cues. MDMA treatment occurred after fear conditioning and 2 h before extinction learning. Extinction recall was tested 23 h after MDMA intake. Additional outcome measures included subjective effects, emotion recognition tasks, plasma levels of oxytocin, and pharmacokinetics. Results: Fear conditioning and extinction learning were successful in both fear extinction paradigms (generalized eta–squared [ges] for SCR: 0.08; FPS: 0.07). Compared to placebo treatment, MDMA treatment significantly reduced SCRs to the reinforced conditioned stimulus (CS+) during extinction learning (ges = 0.03) and recall (ges = 0.06). Intensity of the subjective effects of MDMA (good effect, trust, and openness) during extinction learning negatively correlated with the discrimination between CS+ and the safety stimulus (CS−) during recall. MDMA did not influence FPS to conditioned cues. Oxytocin concentration was increased fourfold on average by MDMA during acute effects but was not associated with fear extinction outcomes. Conclusions: MDMA treatment facilitated rapid fear extinction and retention of extinction as measured by SCR to fear cues, in line with animal studies of MDMA facilitation of extinction. However, this effect may be limited to certain forms of learned fear responses, as it was not observed in the extinction model using startle reactivity as the outcome. This study provides further evidence for the facilitation of extinction with MDMA treatment and suggests this may be a component of its efficacy when paired with psychotherapy. Clinical Trial registration: clinicaltrials.gov identifier: NCT03527316

Neural, physiological, and psychological markers of appetitive conditioning in anorexia nervosa: a study protocol

BackgroundAnorexia nervosa (AN) is a chronic and disabling psychiatric condition characterized by low hedonic drive towards food, and is thought to be inclusive of altered dimensions of reward processing. Whether there exists a fundamental aberrancy in the capacity to acquire and maintain de novo hedonic associations—a critical component of hedonic responding—has never been studied in AN.MethodsThis multi-modal study will employ a 2-day Pavlovian appetitive conditioning paradigm to interrogate the (1) acquisition, (2) extinction, (3) spontaneous recovery and (4) reinstatement of appetitive learning in adolescents and young adults with AN. Participants will be 30 currently ill, underweight individuals with AN; 30 weight-restored individuals with AN; and 30 age-matched healthy controls, all aged 12–22 years. All subjects will undergo clinical assessment, followed by the 2-day appetitive conditioning task during which fMRI, pupillometry, heart rate deceleration, and subjective ratings will be acquired.DiscussionThis study will be the first to interrogate appetitive conditioning in AN—a disorder characterized by altered hedonic responding to food. Results will help establish objective biomarkers of appetitive conditioning in AN and lay the groundwork for developing novel lines of treatment for AN and other psychiatric disorders involving diminished ability to experience pleasure and reward.Trial registration: Pending.Intended registry Clinicaltrials.gov.

"Generalized unsafety" as fear inhibition to safety signals in adults with and without childhood trauma.

The Generalized Unsafety Theory of Stress posits that low heart rate variability contributes to a perception of "generalized unsafety" (i.e., constantly perceiving oneself to be unsafe), independent of stressful events or stress-related symptomatology. We tested this claim by examining if resting heart rate variability, trait worry, posttraumatic stress symptoms, trauma history, and age of onset predicted fear inhibition, a measure of generalized unsafety. A Pavlovian discriminant conditioning paradigm was used to assess fear inhibition level by comparing eyeblink startle potentiation to a threat cue (presented with air blast) with startle potentiation to a safety signal (never presented with air blast). Survey and laboratory responses were collected from 42 adults who were 20 years old on average, 86% Women, and 76% White. Heart rate variability did not independently predict variation in fear inhibition, as hypothesized. Rather, higher levels of posttraumatic stress symptoms and greater cumulative interpersonal trauma predicted lower fear inhibition. Individuals reporting childhood trauma had higher trait worry, which predicted more severe posttraumatic stress symptoms. These findings highlight the role of attenuated inhibitory learning in stress-related symptomatology and developmentally disruptive trauma. Ability to distinguish threat from safety is a plausible biobehavioral mechanism by which adversity impacts development.

History-dependent dopamine release increases cAMP levels in most basal amygdala glutamatergic neurons to control learning.

Dopaminergic inputs to basal amygdala (BA) instruct learning of motivational salience. This learning depends on intracellular plasticity signals such as cyclic adenosine monophosphate (cAMP), which is regulated by activation of dopamine receptors. We examine the dynamics of dopamine release and downstream signaling during multiple salient events occurring within tens of seconds. We perform real-time tracking and manipulation of cAMP in BA neurons invitro and invivo. Optogenetically evoked release of dopamine drives proportional increases in cAMP in almost all BA glutamatergic neurons, suggesting widespread actions of dopamine across neurons preferring positive or negative valence. This cAMP response decreases across trials with short intertrial intervals owing to depression of dopamine release. No such depression is evident when photostimulating cAMP production directly. cAMP and protein kinase A responses to repeated appetitive or aversive stimuli also exhibit pronounced depression. Thus, history-dependent dynamics of dopamine and cAMP may regulate learning of temporally clustered, salient stimuli.

Adult age-related differences in appetitive and aversive associative learning.

This study investigated age differences in appetitive and aversive associative learning using a Pavlovian conditioning paradigm. Appetitive and aversive associative learning is the process by which an initially neutral cue is systematically paired with an aversive or appetitive outcome, eventually itself prompting aversive or appetitive responses. Mimicking the motivational shift from a primary gain orientation in young adulthood toward a stronger orientation toward loss prevention in old age, we expected older adults to learn associations between novel stimuli and losses more rapidly than associating neutral cues with gains (here: donations to charity). A pilot study (N = 214, 18-81 years) established the equivalence of monetary gains and losses for a charitable donation across adulthood. Based on these data, an experiment using an associative conditioning paradigm assessed the extent and temporal dynamics of appetitive and aversive learning across adulthood (N = 122, 19-80 years). Results suggest that younger adults form gain-related associations at a higher learning rate compared to losses. By contrast, with increasing age, adults more rapidly track the valence of conditioned stimuli with losses than gains. This differential learning pattern cannot be attributed to age-differences in arousal or expectancy. Results suggest that the negative valence of losses drives learning more efficiently in older age groups, while younger age groups are more sensitive to the positive valence of gains. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spreading depolarization induced by amygdala micro-injury prevents disruption of fear memory extinction in rats

Spreading depolarization (SD), a self-propagating wave of near-complete breakdown of the transmembrane ion gradients with water influx, regularly occurs in traumatized human brain. Here, we investigated long-term neurobehavioral consequences of injury-triggered SDs. Recently, we revealed that SD is reliably triggered by micro-injury of the amygdala, a key brain structure involved in fear processing. Using the classical Pavlovian fear conditioning paradigm, we investigated effects of the post-retrieval amygdala micro-injury and associated SD on fear memory in rats. We found that neither SD nor micro-injury alone affect fear response 24 h later but profoundly change it in subsequent extinction phase. If bilateral injury of the amygdala did not induce SD, fear extinction was severely impaired, while conditioned fear in rats with the identical amygdala injury triggering SD was successfully extinguished similarly to naïve rats. Our study provides first experimental evidence for involvement of injury-induced SD in extinction of traumatic fear memory.